Pancreatic cancer is among the most lethal of human malignancies, with a five year survival rate of ~4%. The overwhelming majority of pancreatic cancers have activating KRAS mutations; however, therapy targeting KRAS has been difficult. In the current study, Feldmann and colleagues show that inhibition of cyclin-dependent kinase 5 (CDK5) in pancreatic cancer cells results in decreased tumorigenicity and metastasis, mediated through suppression of Ras signaling through the Ral effector pathway. In this figure, Feldmann and colleagues show that inhibition of CDK5 in MIAPaCa-2 pancreatic cancer cells induces cytoskeletal changes and loss of polarity. For details, see the article by Feldmann and colleagues on page 4460 of this issue.